It is believed that most people with HIV infection will ultimately develop clinical AIDS. Furthermore, death from the complications of AIDS often occurs within months or years after clinical AIDS is diagnosed. Most HIV infected people remain healthy for many years despite the infection. Likewise, some people with past clinical diagnosis continue to live productive lives for many years after first developing clinical AIDS.
Among HIV-1 infected individuals, the duration of the asymptomatic period after seroconversion may differ considerably (refs. 1 to 3--throughout this specification, various references are referred to in parenthesis to more fully describe the state of the art to which this invention pertains. Full bibliographic information for each citation is found at the end of the specification, immediately preceding the claims. The disclosures of these references are hereby incorporated by reference into the present disclosure). Mechanisms suggested to play a role in long-term survival include viral characteristics, as well as host genetic and immunological factors. However, immunological correlates of AIDS-free survival have not been identified conclusively (refs. 1 and 3).
The human immunodeficiency virus type 1 (HIV-1) and related lentiviruses have more complex genomes than typical retroviruses. In addition to the gag, pol and env genes common to all retroviruses, HIV-1 also encodes genes for tat, rev, nef, vif, vpu, and vpr. The HIV-1 protein REV (regulator of expression of the virion) plays an essential role in the temporal regulation of virus gene expression during a replication cycle. The genes expressed by HIV-1 can be separated into two groups based on whether their expression is Rev-dependent or not. The Rev-independent or early genes encode Tat, Rev, and Nef. The Rev-dependent or late genes are important for virion production and encode the structural proteins Gag, Pol and Env and the accessory products Vif, Vpu and Vpr. Rev is absolutely required for HIV-1 replication. Proviruses that lack Rev function remain transcriptionally active, but fail to generate new viral particles. The biology of the Rev protein is summarized in reference 30.
Cis- and trans-acting elements which regulate HIV gene expression have been identified. An 86 amino acid viral protein, Tat is required for HIV-1 gene expression and for subsequent viral replication. Tat is unique among viral transactivators. Unlike ElA and Tax, which activate a number of viral and cellular genes, Tat activation is relatively specific for HIV-1. A cis-acting element in the HIV-1 LTR, located downstream of the RNA initiation site, is critical for high-level gene expression. This element, which extends from +1 to +60 in the HIV-1 LTR, was designated the trans-acting response element, or TAR. TAR forms a double-stranded RNA structure which is required for high-level gene expression in response to Tat. The function of Tat is described in reference 31.
The present invention is concerned with the role of HIV-1 specific cytotoxic T lymphocytes (CTL) in this long-term survival. In previous studies, CTL specific for the structural proteins Gag and RT have been detected in at least 80% of seropositive individuals (refs. 4 to 9), whereas CTL against Nef and Vif have been reported in approximately 50% of seropositive individuals (refs. 10 to 12). These studies have also indicated that the regulatory proteins Rev and Tat are less frequently recognized (refs. 10 to 12). Cross-sectional studies have shown that HIV-1 specific CTL precursors (CTLp) are generally present in the asymptomatic stage, but their frequencies tend to be low in advanced disease (refs. 13, 14). Longitudinal analyses have shown that HIV-1 specific CTL responses are associated with initial control of viremia (ref. 15) and that Gag specific CTLp decline with disease progression, probably as a result of HIV-1 induced CD4.sup.+ cell decline (refs. 16, 17) and cytokine dysfunction (ref. 17). Viral loads have been shown to be predictive of disease progression and can be measured by commercially available tests (refs. 18, 19).
Furthermore, there are no commercially available immunological tests to determine favourable prognosis of a patient infected with HIV.
There is a need for laboratory tests that identify those HIV infected patients who are more likely to have a favourable prognosis, slower disease progression, and stable disease compared with those patients who are likely to have poor prognosis, or more rapid disease progression.
Infection with HIV leads to a serious immunodeficiency disease, AIDS. There is no cure for AIDS nor any vaccine against infection and the disease. It would be desirable to provide methods and compositions (including immunogenic compositions, such as vaccines) for the prevention and treatment of AIDS. It would also be desirable to provide test procedures and materials to identify those patients who are likely to have a favourable prognosis and a slower disease progression.